Obesity has reached epidemic proportions in the United States and is closely linked to type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). For centuries, Ayurveda has recommended the use of Momordica charantia or bitter melon (BM) as a functional food to prevent and treat diabetes and associated complications. In humans, consumption of BM reduced glucose tolerance and postprandial glucose in diabetic patients as well as glycosylated hemoglobin. In animal studies, we, and others have demonstrated that BM not only improves glucose metabolism, but also reduces body fat, plasma triglyceride (TG), cholesterol, and very low density lipoprotein (VLDL) levels. We recently demonstrated that BM juice (BMJ) reduces apolipoprotein B (apoB), apoC-III and TG synthesis, and secretion in human liver cells, HepG2. Our preliminary data indicates that BMJ improves hepatic insulin signaling cascade and activates the mammalian longevity gene, sirtuin (Sirt1). Our long-term goal is to understand the molecular mechanisms of functional foods to ameliorate obesity and associated metabolic disorders of diabetes and dyslipidemia. The objective of the proposed research is to investigate the molecular targets and pathways of BM-associated Sirt1 activation and mechanisms of TG and apoB regulation as well as to characterize active components of BMJ based on bioactivity-guided fractionation. Based on the fact that Sirt1 improves lipid and glucose metabolism via forkhead transcription factors (Foxo) and our preliminary data that BMJ increases Sirt1 protein in mouse liver, we hypothesize that BMJ regulates hepatic TG and glucose metabolism via Sirt1 activation, specifically through Foxo pathways. We will employ bioactivity-guided fractionation of BMJ to identify the active components which will be used to test our hypothesis using in-vivo and ex-vivo experiments. Our specific aims are to investigate the effects of BMJ-associated- 1) Sirt1 activation on Foxo proteins to regulate TG and glucose metabolism, and 2) -activation of PI3K pathway to regulate apoB metabolism. This is a unique and novel study, which will demonstrate that functional foods have the capacity to regulate the longevity gene, Sirt1. Knowledge obtained from this study is expected to be utilized to conduct translational research in humans to alleviate diabetic dyslipidemia. Traditional functional foods will be readily acceptable by culturally sensitive population, will improve quality of life, and will offer a cost-effective treatment or preventive strategy for diabetic dyslipidemia globally. Understanding molecular events of functional foods has strong potential for developing drugs for obesity- associated metabolic disorders. "Going back to our cultural roots" and identifying foods with not only nutritional but also medicinal/functional properties, may have a significant impact on promoting health and longevity by reducing morbidity and mortality associated with obesity and associated disorders of type 2 diabetes and cardiovascular diseases. [unreadable] [unreadable] [unreadable] [unreadable]